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Tricyclic compound and application thereof

A compound, cycloalkyl technology, applied in the field of chemical medicine, can solve problems such as single structure, and achieve the effect of inhibiting proliferation, good inhibitory effect, and novel structure

Pending Publication Date: 2021-07-16
SHANGHAI LITEDD CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the defect of single structure of existing HDAC inhibitors, especially HDAC6 inhibitors, and provide a tricyclic compound and its use

Method used

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  • Tricyclic compound and application thereof
  • Tricyclic compound and application thereof
  • Tricyclic compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Example 1: N-(7-(Hydroxyamino)-7-oxoheptyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole- 2-formamide

[0118]

[0119] Step 1: Preparation of tert-butyl 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0120] Phenylhydrazine hydrochloride (5.00g, 34.6mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (8.3g, 4.15mmol) were added to acetic acid (50mL), and the reaction mixture was stirred at 65°C to react 16 hours. Concentrate under reduced pressure to remove the organic solvent. Add water (50 mL) to dilute, and extract with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation and purification by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1-5:1) gave the target compound (5.3 g, yield 56.3%, yellow solid). LC-MS(ESI)m / z[M+H] ...

Embodiment 2

[0127] Example 2: N-(7-(hydroxyamino)-7-oxoheptyl)-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3- b] indole-2-carboxamide

[0128]

[0129] Step 1: Preparation of tert-butyl 5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0130] Dissolve tert-butyl 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (500 mg, 1.84 mmol) in N,N-dimethylformamide ( 5 mL), iodomethane (287 mg, 2.02 mmol) and potassium hydroxide (310 mg, 5.52 mmol) were added. The reaction mixture was stirred at 60°C for 16 hours. Water (10 mL) was added to the reaction mixture for dilution, and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation and purification by column chromatography (silica gel, petroleum ether: ethyl acetate = 20:1-5:1) gave the target compound (300 mg, yield 57.0%,...

Embodiment 3

[0137] Example 3: N-(7-(hydroxyamino)-7-oxoheptyl)-5-isopropyl-1,3,4,5-tetrahydro-2H-pyrido[4, 3-b] indole-2-carboxamide

[0138]

[0139] Step 1: Preparation of tert-butyl 5-isopropyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0140] Dissolve tert-butyl 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.734 mmol) in N,N-dimethylformamide ( 5mL). Sodium hydride (60%, 32.3 mg, 0.807 mmol) was added at 0 °C. The reaction mixture was stirred at 0°C for half an hour and then 2-iodopropane (137 mg, 0.807 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding water (10 mL) at 0°C, extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The target compound (120 mg, yield 52.0%, colorles...

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Abstract

The invention discloses a tricyclic compound and application thereof. The invention specifically discloses a compound as shown in a formula I or pharmaceutically acceptable salt thereof. The tricyclic compound disclosed by the invention has a very good inhibition effect on HDAC (histone deacetylase), especially HDAC6, has relatively good selectivity and can be used for inhibiting proliferation of various tumor cells.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and specifically relates to a tricyclic compound and its application. Background technique [0002] Epigenetic modification plays a very important role in the process of gene expression regulation, and histone deacetylases (HDACs), as an important functional protein of epigenetic regulation, have attracted scientists in recent decades widespread attention. On the one hand, HDACs can mediate the deacetylation of histone substrate lysine, which is conducive to the formation of a more compact structure of chromatin, and some HDACs can interact with other chromatin regulatory proteins to form co-repression complexes, Thus regulating gene expression, cell cycle and cell differentiation and other life processes; on the other hand, some HDACs can also catalyze the deacetylation of non-histone substrate lysine, thus playing an important role in more cell regulatory pathways ( Nat Biotech...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D209/88C07D209/94C07D487/04C07D401/04A61K31/437A61K31/403A61K31/506A61K31/444A61K31/497A61K31/4439A61K31/407A61P35/00A61P37/00A61P35/02A61P19/02A61P19/00A61P17/06A61P9/10A61P1/00A61P11/00A61P17/00A61P11/06A61P1/04A61P19/06A61P13/12A61P37/06A61P5/00A61P37/08A61P29/00
CPCC07D471/04C07D209/88C07D209/94C07D487/04C07D401/04A61P35/00A61P37/00A61P35/02A61P19/02A61P19/00A61P17/06A61P9/10A61P1/00A61P11/00A61P17/00A61P11/06A61P1/04A61P19/06A61P13/12A61P37/06A61P5/00A61P37/08A61P29/00
Inventor 程耀邦王永辉董志强栗增沈孝坤
Owner SHANGHAI LITEDD CO LTD
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